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AR061567A1 - PURE COMPOUNDS ENANTIOMERICALLY FOR THE TREATMENT OF PROLIFERATIVE DISORDERS - Google Patents

PURE COMPOUNDS ENANTIOMERICALLY FOR THE TREATMENT OF PROLIFERATIVE DISORDERS

Info

Publication number
AR061567A1
AR061567A1 ARP070102738A ARP070102738A AR061567A1 AR 061567 A1 AR061567 A1 AR 061567A1 AR P070102738 A ARP070102738 A AR P070102738A AR P070102738 A ARP070102738 A AR P070102738A AR 061567 A1 AR061567 A1 AR 061567A1
Authority
AR
Argentina
Prior art keywords
alkyl
substituted
unsubstituted
alkylenehydroxy
alkoxycarbonyl
Prior art date
Application number
ARP070102738A
Other languages
Spanish (es)
Original Assignee
Nicholas Piramal India Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nicholas Piramal India Ltd filed Critical Nicholas Piramal India Ltd
Publication of AR061567A1 publication Critical patent/AR061567A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Virology (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Se refiere además a intermediarios puros enantioméricamente de la misma, para procesos para la preparacion del compuesto puro enantioméricamente y sus intermediarios, y para una composicion farmacéutica que comprende el compuesto puro enantioméricamente. El compuesto de la formula (1) es util para el tratamiento de enfermedades o desordenes transmitidos por la inhibicion de la ciclina dependiente de la quinasa, como ser el cáncer. Reivindicacion 1: Compuesto puro enantioméricamente representado por la siguiente formula (1) o un metabolito, prodroga, sal farmacéuticamente aceptable, solvato farmacéuticamente aceptable o polimorfo de los mismos; en donde R1 es fenilo, que se encuentra no sustituido o sustituido por 1, 2, o 3 sustituyentes idénticos o diferentes seleccionados de: halogeno, nitro, ciano, alquilo C1-4, fluorometilo, difluorometilo, trifluorometilo, alcoxi C1-4, hidroxilo, carboxi, alcoxicarbonilo C1-4, alquilenohidroxilo C1-4, CONH2, CONR5R6, SO2NR5R6, cicloalquilo, NR5R6 y SR7; o es un heterociclo, que es un anillo saturado, parcialmente no saturado o aromático que contiene cinco o seis átomos en el anillo de los cuales 1, 2 o 3 son heteroátomos idénticos o diferentes seleccionados de: nitrogeno, oxígeno y azufre, y donde el heterociclo se encuentra no sustituido o sustituido por 1, 2, o 3 sustituyentes idénticos o diferentes seleccionados de: halogeno, nitro, ciano, alquilo C1-4, fluorometilo, difluorometilo, trifluorometilo, alcoxi C1-4, hidroxilo, carboxi, alcoxicarbonilo C1-4, alquilenohidroxilo C1-4, CONH2, CONR5R6, SO2NR5R6, cicloalquilo, NR5R6 y SR7; en donde R5 y R6 se seleccionan independientemente de: hidrogeno, alquilo C1-4, alcoxicarbonilo C1- 4, alquilcarbonilo C1-4, arilo; o R5 y R6 juntos con el átomo de nitrogeno al cual están unidos podrán formar un anillo de cinco o seis miembros que podrá contener opcionalmente un heteroátomo adicional; y R7 podrá seleccionarse de hidrogeno, alquilo C1-4, arilo, SR10 en donde R10 podrá seleccionarse de alquilo C1-4, alquilo o arilo; R2 y R3 se seleccionan independientemente de: halogeno, hidroxilo y OR8; en donde R8 se encuentra sustituido o no sustituido por alquilo C1-10, alcanoil C1- 4, aroil sustituido o no sustituido; R4 es alquilenohidroxilo C1-4; y R9 es hidrogeno o alquilo C1-4.It also refers to enantiomerically pure intermediates thereof, for processes for the preparation of the enantiomerically pure compound and its intermediates, and for a pharmaceutical composition comprising the enantiomerically pure compound. The compound of the formula (1) is useful for the treatment of diseases or disorders transmitted by the inhibition of cyclin dependent kinase, such as cancer. Claim 1: Pure compound enantiomerically represented by the following formula (1) or a metabolite, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or polymorph thereof; wherein R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from: halogen, nitro, cyano, C1-4 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, C1-4 alkoxy, hydroxyl , carboxy, C1-4 alkoxycarbonyl, C1-4 alkylenehydroxy, CONH2, CONR5R6, SO2NR5R6, cycloalkyl, NR5R6 and SR7; or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing five or six ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from: nitrogen, oxygen and sulfur, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from: halogen, nitro, cyano, C1-4 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, C1-4 alkoxy, hydroxyl, carboxy, C1- alkoxycarbonyl 4, C1-4 alkylenehydroxy, CONH2, CONR5R6, SO2NR5R6, cycloalkyl, NR5R6 and SR7; wherein R5 and R6 are independently selected from: hydrogen, C1-4 alkyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyl, aryl; or R5 and R6 together with the nitrogen atom to which they are attached may form a five or six membered ring that may optionally contain an additional heteroatom; and R7 may be selected from hydrogen, C1-4 alkyl, aryl, SR10 wherein R10 may be selected from C1-4 alkyl, alkyl or aryl; R2 and R3 are independently selected from: halogen, hydroxyl and OR8; wherein R8 is substituted or unsubstituted by C1-10 alkyl, C1-4 alkanoyl, substituted or unsubstituted aroyl; R4 is C1-4 alkylenehydroxy; and R9 is hydrogen or C1-4 alkyl.

ARP070102738A 2006-06-21 2007-06-21 PURE COMPOUNDS ENANTIOMERICALLY FOR THE TREATMENT OF PROLIFERATIVE DISORDERS AR061567A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2006/052002 WO2007148158A1 (en) 2006-06-21 2006-06-21 Enantiomerically pure flavone derivatives for the treatment of poliferative disorders and processes for their preparation

Publications (1)

Publication Number Publication Date
AR061567A1 true AR061567A1 (en) 2008-09-03

Family

ID=37744533

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP070102738A AR061567A1 (en) 2006-06-21 2007-06-21 PURE COMPOUNDS ENANTIOMERICALLY FOR THE TREATMENT OF PROLIFERATIVE DISORDERS

Country Status (18)

Country Link
US (1) US8563596B2 (en)
EP (1) EP2046738B1 (en)
JP (1) JP5498782B2 (en)
KR (1) KR101209397B1 (en)
CN (1) CN101472888B (en)
AR (1) AR061567A1 (en)
AU (1) AU2006344987B8 (en)
BR (1) BRPI0621777A2 (en)
CA (1) CA2655789C (en)
DK (1) DK2046738T3 (en)
ES (1) ES2491140T3 (en)
IL (1) IL195850A0 (en)
MX (1) MX2008016398A (en)
NZ (1) NZ574266A (en)
PT (1) PT2046738E (en)
TW (1) TWI461420B (en)
WO (1) WO2007148158A1 (en)
ZA (1) ZA200810756B (en)

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US7915301B2 (en) 2002-07-08 2011-03-29 Piramal Life Science Limited Inhibitors of cyclin dependent kinases and their use
US7884127B2 (en) 2002-07-08 2011-02-08 Pirimal Life Sciences Ltd. Inhibitors of cyclin dependent kinases and their use
AU2006346193C1 (en) 2006-07-07 2014-02-20 Piramal Enterprises Limited An enantioselective synthesis of pyrrolidine-substituted flavones
TWI461194B (en) * 2009-05-05 2014-11-21 Piramal Entpr Ltd Pyrrolidine Substituted Flavones as Radio Sensitizers
WO2011097522A2 (en) 2010-02-05 2011-08-11 Whitehead Institute For Biomedical Research Combination methods for treatment of disease
KR20130027476A (en) 2010-02-26 2013-03-15 피라말 엔터프라이지즈 리미티드 Pyrrolidine substituted flavones for the treatment of inflammatory disorders
CA2794676A1 (en) 2010-03-29 2011-10-06 Piramal Enterprises Limited Cytokine inhibitors
WO2012069972A1 (en) 2010-11-19 2012-05-31 Piramal Life Sciences Limited A pharmaceutical combination for the treatment of breast cancer
TW201242597A (en) 2011-03-14 2012-11-01 Piramal Life Sciences Ltd A synergistic pharmaceutical combination for the treatment of pancreatic cancer
UY34013A (en) * 2011-04-13 2012-11-30 Astrazeneca Ab ? CHROMENONE COMPOUNDS WITH ANTI-TUMORAL ACTIVITY ?.
TW201300105A (en) * 2011-05-31 2013-01-01 Piramal Life Sciences Ltd A synergistic pharmaceutical combination for the treatment of squamous cell carcinoma of head and neck
US20140142159A1 (en) 2011-06-24 2014-05-22 Piramal Enterprises Limited Compounds for the treatment of cancers associated with human papillomavirus
US20140348950A1 (en) 2012-01-13 2014-11-27 Piramal Enterprises Limited Pyrrolidine- substituted flavone derivatives for prevention or treatment of oral mucositis
WO2014018741A1 (en) 2012-07-27 2014-01-30 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
KR101389407B1 (en) * 2012-08-27 2014-05-27 한림대학교 산학협력단 Implant for spine fixation
WO2014049515A1 (en) * 2012-09-25 2014-04-03 Piramal Enterprises Limited Pyrrolidine substituted flavones for treatment of renal cystic diseases
EP3369730B1 (en) 2012-11-05 2020-08-05 Emory University 7,8-dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto
US20140199728A1 (en) 2013-01-14 2014-07-17 Amgen Inc. Methods of using cell-cycle inhibitors to modulate one or more properties of a cell culture
WO2014128524A1 (en) * 2013-02-19 2014-08-28 Piramal Enterprises Limited An improved process for preparation of an intermediate of the pyrrolidine substituted flavones
WO2014128523A1 (en) * 2013-02-19 2014-08-28 Piramal Enterprises Limited A process for preparation of an intermediate of the pyrrolidine substituted flavones
WO2014140695A1 (en) * 2013-03-15 2014-09-18 Piramal Enterprises Limited Solid oral formulation of a pyrrolidine substituted flavone compound
CN117731786A (en) 2013-07-12 2024-03-22 皮拉马尔企业有限公司 Pharmaceutical combination for the treatment of melanoma
DK3148532T3 (en) 2014-05-28 2021-04-26 Piramal Entpr Ltd Pharmaceutical Combination Comprising a CDK Inhibitor and a Thioredoxin Reductase Inhibitor for the Treatment of Cancer
NZ757763A (en) 2016-03-28 2025-07-25 Presage Biosciences Inc Pharmaceutical combinations for the treatment of cancer
HUE066348T2 (en) 2018-08-07 2024-07-28 Univ Emory Heterocyclic flavone derivatives, compositions, and methods related thereto
AU2019322858A1 (en) * 2018-08-14 2021-04-01 Mei Pharma, Inc. Combination therapy
CN113195000A (en) 2018-12-21 2021-07-30 第一三共株式会社 Combination of antibody-drug conjugates and kinase inhibitors
CA3136599A1 (en) * 2019-04-11 2020-10-15 Mei Pharma, Inc. Voruciclib poly morphs and methods of making and using thereof
CN110028475B (en) * 2019-05-13 2022-07-01 中国药科大学 Novel CDK9 inhibitor based on benzopyran structure, its preparation method and application
IL302925A (en) * 2020-11-19 2023-07-01 Mei Pharma Inc Treatment of KRAS mutant cancers
CN114957182B (en) * 2022-03-30 2024-03-15 中国药科大学 USP8 inhibitor containing flavone skeleton structure and application thereof

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IN164232B (en) 1986-04-11 1989-02-04 Hoechst India
JP3451099B2 (en) 1991-12-06 2003-09-29 株式会社日立製作所 External storage subsystem
TWI331034B (en) * 2002-07-08 2010-10-01 Piramal Life Sciences Ltd Inhibitors of cyclin-dependent kinases and their use
US7271193B2 (en) * 2002-07-08 2007-09-18 Nicholas Piramal India, Ltd. Inhibitors of cyclin-dependent kinases and their use
US8017651B2 (en) 2002-11-22 2011-09-13 Bionexus, Ltd. Compositions and methods for the treatment of HIV-associated fat maldistribution and hyperlipidemia

Also Published As

Publication number Publication date
AU2006344987B8 (en) 2013-07-11
PT2046738E (en) 2014-08-29
AU2006344987A2 (en) 2009-01-29
HK1126761A1 (en) 2009-09-11
AU2006344987B2 (en) 2012-11-15
CA2655789A1 (en) 2007-12-27
NZ574266A (en) 2011-10-28
TW200813030A (en) 2008-03-16
CN101472888A (en) 2009-07-01
MX2008016398A (en) 2009-01-21
WO2007148158A1 (en) 2007-12-27
AU2006344987A1 (en) 2007-12-27
TWI461420B (en) 2014-11-21
KR20090023705A (en) 2009-03-05
ZA200810756B (en) 2013-05-29
EP2046738A1 (en) 2009-04-15
CA2655789C (en) 2014-04-01
KR101209397B1 (en) 2012-12-06
ES2491140T3 (en) 2014-09-05
JP5498782B2 (en) 2014-05-21
US20100179210A1 (en) 2010-07-15
JP2009541294A (en) 2009-11-26
CN101472888B (en) 2014-02-26
BRPI0621777A2 (en) 2013-03-12
IL195850A0 (en) 2009-09-01
EP2046738B1 (en) 2014-06-11
DK2046738T3 (en) 2014-08-04
US8563596B2 (en) 2013-10-22

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